In order to be suitable for a particular use, a substrate often needs to be adapted to a particular environment by changing its character, for example, inuring it with properties such as biocompatability, specific gas permeability, or a low friction coefficient, without significant alteration of the underlying substrate.
Biomedical devices such as catheters, oxygenators, grafts, and stents require biocompatability. These devices are used to provide inter alia drug delivery, gas exchange, or mechanical support to various portions of the human or animal body. In their normal application, such devices are expected to function in intimate contact with living tissue and blood. This interface creates a delicate balance between ensuring that the device can function in the complex extra- and intra- cellular environment and maintaining the living tissues and blood. By use of the compositions of the present invention devices, which might otherwise be rejected by living tissue, are rendered biocompatible, that is, acceptable and functional within a human or animal body.
1. Thrombus Formation Results In The Occlusion Of Biomedical Devices
Thrombus formation, the formation of a blood clot, may be a serious and potentially debilitating response to synthetic substrates in contact with blood or tissue. When blood or tissue contacts the substrate surface, proteins in the blood or tissue may be adsorbed by the surface.
The initial protein layer of the blood/substrate interface is subject to denaturation, replacement, and further reaction with blood components. The composition and conformation of the adsorbed proteins may influence the occurrence of subsequent cellular responses such as platelet adhesion, aggregation, secretion, and complement activation. Adsorbed fibrinogen may be converted to fibrin, the fibrous insoluble protein that forms the structure of a thrombus. Fibrin formation is accompanied by adherence of platelets and possibly leukocytes. The platelets are activated and release the contents of their granules, resulting in activation of other platelets, and ultimately resulting in platelet aggregation.
A thrombus eventually forms from entrapment of platelets, erythrocytes and other blood constituents in the growing fibrin network. Thrombus growth can lead to partial or total blockage of the device. Additionally, the thrombus may be sheared off or lysed, or otherwise released from the substrate as an embolus, a mass of particulate matter. Unfortunately, emboli can be as dangerous as device blockage. Emboli can travel throughout the bloodstream and lodge in vital organs, thus, causing infarction, the localized death of tissue due to the obstructed blood flow. Infarction of the heart, lungs, or brain can be fatal.
Long term use of most polymeric substrates has inevitably resulted in mechanical failure, the promotion of blood clot formation, or physical degradation due to unfavorable interactions with tissue or blood environment. P. Vondracek, et al., "Biostability of Medical Elastomers: A Review," Biomaterials, 5:209-214 (1984); D. F. Williams, "Biodegradation of Surgical Polymers," J. Natr. Sci., 17:1233-1246 (1982). The present invention plays an important role by inhibiting thrombus formation, embolization, and protein denaturation, thereby allowing biomedical devices made from numerous different substrates to be useful, functioning tools.
2. Biomedical Devices Are Frequently Subject To Degradation Due To The Nature Of The Working Environment
Most biomedical devices are manufactured from polymeric substrates. As a result, they are susceptible to degradation. D. K. Gilding, "Fundamental Aspects of Biocompatability," Vol. I, ed. D. F. Williams, CRC Press, Boca Raton, Fla. (1981). There are any number of ways in which degradation may occur. The substrate may be susceptible to hydrolysis. Polymeric devices in contact with aqueous extracellular fluid are particularly susceptible to degradation by hydrolysis when the polymer is hydrophilic, contains hydrolytically unstable bonds, and the pH remains around 7.4. Substrates with soft silicon coatings may be susceptible to leaching into the surrounding tissues.
3. To Date There Have Been No Safe Long Term Methods For Altering The Substrate Characteristics To Adapt To The Working Environment
Device failure is both costly and hazardous to human life. Thus, a variety of measures have been attempted to avoid these problems. Systemic anticoagulants, such as heparin and warfarin, have been directly administered to the subject having the device in order to combat thrombosis; however, such anticoagulant therapy has a risk of hazardous side effects. Moreover, overdoses of anticoagulants may cause lethal side reactions, such as visceral or cerebral bleeding. Other measures involve regular flushing of silicon and polyurethane catheters with heparinized saline or frequent replacement of the implanted catheters before thrombosis occludes. Such measures are both time consuming and expensive.
Pyrolytic carbon coatings have been used successfully in conjunction with long term implants such as artificial heart valves. Haubold, A. D., et al., "Carbon Biomedical Devices" in Biocompatability of Clinical Implant Materials, Vol. II, CRC Press, Boca Raton, 3-42 (1981). The pyrolytic carbon thinly coated on the artificial heart valves has been shown to function in the human body for as long as ten years without major complications. Unfortunately, in order to coat biomedical devices with pyrolytic carbon, the surface of the substrate to be coated must be able to withstand temperatures above 900.degree. C. Most polymeric materials suitable for biomedical devices decompose at temperatures above 400.degree. C.
Substrate surfaces have been coated via adsorption of hydrophilic or segmented hydrophilic/hydrophobic polymers to minimize protein adhesion and platelet adhesion/activation.
4. Thromboresistance and Biocompatibility Are Often Only The First In A Long List Of Required Characteristics.
For certain uses other properties are required besides substrate biocompatibility or thromboresistance. The specific requirements of each device may vary in accordance to the degree and duration of contact and the nature of the application. Oxygenators, for example, require superior gas permeability. These devices facilitate the exchange of oxygen and carbon dioxide by transferring oxygen from the inner lumen of a polypropylene or polyethylene microporous fiber through the cross section, via microporous holes, into the blood at the fiber/blood interface. Plasma leakage through the microporous membranes of conventionally used oxygenators, (such as Sarns, model 16310N3; Medtronic Maxima and Minimax) has been reported after prolonged exposure to blood and has been thought to be associated with serum triglyceride levels. Adsorption of bipolar plasma molecules such as phospholipids on the hydrophobic microporous membrane has been thought to form a hydrophilic layer over the hydrophobic membrane surface leading to surface wetting and plasma leakage through the microporus membrane. See J. Patrick Montoya, et al., ASAIO J., M399-M405 (1992). Usually within a few hours of exposure to blood, the plasma leakage through the microporous membrane will drastically reduce the gas transfer ability of the oxygenator. At that point the whole device must be discarded and replaced in order to avoid serious consequences to the patient.
Artificial vision or hearing implant devices require substrates with insulating properties. The liquid saline environment is highly corrosive to metals, which, being under electrical bias, are subject to rapid failure due to electrochemical reactions. Furthermore, most polymeric substrates suitable for these devices are subject to an incompatible interface between the polymer and the silicon electrode surface. Yamamoto, M. et al, Applied Polymer Science, 29:2981 (1984). The membrane coating of the present invention provides the substrate with the necessary insulating properties. In addition, the membrane provides excellent interfacial adhesion with metal (FIG. 18) and silicon substrates, rendering them ideal for protective, insulating coatings and biocompatible coatings.
It is clear from the foregoing that biocompatible blood or tissue contacting surfaces comprise an urgently need in the biomaterials industry to counteract a wide variety of blood or tissue/material incompatibility reactions. A number of the embodiments of the present invention foster biocompatability of all substrate surfaces. Other embodiments will capitalize on altering substrate characteristics to harmonize with their environment.